Growing evidence suggests that pathways in addition to inflammation and dyslipidemia contribute to the Underlying processes of atherosclerosis, endothelial dysfunction, and premature coronary heart disease (CHD). However, few studies have examined the interrelations between oxidative stress, endothelial dysfunction, and CHD. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS), and has recently emerged as a potential novel risk marker for cardiovascular disease. The majority of ADMA is metabolized by the enzyme, dimethylarginine dimethylaminohydrolase (DDAH), and increased cellular oxidative stress inhibits DDAH activity in the tissues, which leads to sustained levels of ADMA. Accumulation of ADMA and reduced NO systhesis leads to endothelial dysfunction and also initiates and promotes processes involved with atherogenesis. Plasma ADMA levels have been associated with several risk factors of CHD;however, data on the predictive value of ADMA, genetic variation in the DDAH gene, and the prospective risk of CHD in men and women have thus far been limited. The goal of this proposal is to investigate plasma ADMA levels as a novel biochemical predictor of CHD among two large prospective cohort studies: the Nurses Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Both studies have over 22 years of repeated dietary and lifestyle questionnaire data, blood samples collected from 32, 826 women in NHS and 18,225 men in HPFS, and nested case-control studies with biological specimens previously archived among incident cases of nonfatal myocardial infarction or fatal CHD, and age and smoking matched controls. The specific aims of this proposal are to: 1) examine the prospective relationship between plasma ADMA and risk of incident CHD in nested case-control settings among men and women;2.) utilize the existing prospective data to examine interrelations between lifestyle, dietary, and other health factors, and plasma ADMA to elucidate potential mechanisms;and 3.) examine the genetic variation on the DDAH gene with plasma ADMA levels and risk of CHD in both men and women. These findings may lead to new therapeutic interventions which inhibit the effects of ADMA and prevent the progression of atherosclerosis and cardiovascular disease.